Description of Related Art
Publications and other materials used to illuminate the Background, Summary and Detailed Description of the Invention are incorporated herein by reference.
The application of this invention is directed primarily to the life threatening situations encountered in the trauma centers and operating rooms, where prompt action is essential. Current practices of performing blood analysis in the laboratory or in equipment which require from one quarter of an hour or more to provide results is in many cases inadequate and the patient's life is placed in jeopardy due to this delay.
To facilitate the analysis of the blood of an individual, and specifically the ionic concentration of several ionic components of the blood, the system described herein accomplishes this task in a superior manner over similar prior art devices. The analysis of the ionic concentration in blood require special sensors which can respond selectively to the particular ion of which the concentration is being measured.
As the skilled artisan will readily appreciate, the ionic concentration within blood plays a dominant role in the health of an individual, and therefore, fluctuations in the ionic concentration of certain ionic compounds can have serious implications for the individual. For example, in patients with arrhythmias, cardiac shock, and myocardial infarctions, such ionic concentrations may change substantially over the course of treatment of a patient, and the measurement of such change in ionic concentration can provide critical information with respect to the well being of the patient. Ionic concentrations may also change during the course of surgery, during pharmacological therapy, the administration of fluid and electrolytes to the patient, and during other types of medical treatments and procedures. In all of the above scenarios, the measurement and monitoring of ionic concentration levels may be, and, in fact, usually is, required on a fairly continuous basis. This of course can create additional problems for the patient in that relatively large quantities of blood must be continually removed and analyzed, and such continuous removal can create patient discomfort, and, depending on the nature of the condition of the patient, may be impossible.
In order to achieve a "real time" analysis of the various concentrations of ions within a patients blood, and hence obtain more accurate values for course-of-treatment determinations, the amount of time between when the blood to be analyzed ("analyte") leaves the patient and is analyzed must be minimal. Additionally, the temperature of the analyte should be as close to the temperature of the patient's blood as possible. Finally, in order to limit exsanguination, a system designed for continuous monitoring of ionic concentration for extended periods of time requires the removal of as little blood as possible from the patient.
The current state of the art utilizes selective membranes applied directly to the gate of a field effect transistor in order to analyze the ionic concentration in blood. Such transistors with a selective membrane so applied are known as "ChemFETS." For example, in U.S. Pat. No. 4,180,771, a semiconducting substrate is described having a gate insulator of an electrically insulatory material overlapping a portion of a substrate other than that covered by a gate insulator, such that when the chemically sensitive layer is exposed to a solution, the electric field in the substrate is modified, which changes the conductance of the channel between a source region and drain region. This change in conductance is related to chemical exposure and can be directed with a measuring device, e.g., a current meter. A similar device is also described in U.S. Pat. No. 4,322,680. Reference is also made to U.S. Pat. No. 4,448,556.
In U.S. Pat. No. 4,641,249, there is described a device which compensates for temperature-dependent characteristic changes in ion-sensitive field-effect transistors. Sibbald, Covington and Carter, in "Online patient-monitoring system for the simultaneous analysis of blood K.sup.+, Ca.sup.2+, Na.sup.+ and pH using a quadruple-function ChemFET integrated-circuit sensor" Med & Bio. Eng. & Comp. 23:329-338 (1985) (hereinafter "Sibbald"), describe a continuous on-line system for analyzing blood K.sup.+, Ca.sup.2+, Na.sup.+ and pH whereby a ChemFET device is incorporated into a miniature flow through cell. The system uses a small analyte sample (30 ul). The system also utilizes a pinch-tube sampling valve, a heat exchanger and a reference electrode. An analyte-chopping analysis (ACA) system is also utilized in which analyte samples are sent to the ChemFET in alternation with a calibration solution which is chosen to provide baseline ion concentration levels such that each calibration solution acts as a reference datum for the evaluation of the data from the analyte samples. A microcomputer controls the alternating flow of blood and baseline solution through the ChemFET See also, Sibbald, Covington & Cooper, "On-Line Measurement of Potassium in Blood by Chemical-Sensitive Field Effect Transistor: A Preliminary Report" Clin. Chem 29:405-06 (1983) and U.S. Pat. No. 4,502,938. The system is not, however, without serious problems relative to the objective of the system, i.e., an accurate, real-time analysis of the ionic concentration levels of an individual's blood.
As noted in Sibbald, supra, ChemFET devices exhibit some thermal sensitivity. Thus, fluctuation in analyte temperature (caused by the difference in temperature between the baseline solution at ambient and blood at body temperature) can interfere with the sensitive analysis of the ChemFET. Additionally, and not discussed in Sibbald, is that the use of a 12V solenoid valve for closing the tubing lines inherently generates heat within close proximity to the ChemFET. In order to compensate for the problems of "heat," Sibbald describes the use of a small glass heat exchanger, whereby blood passes down a narrow central portion of the exchanger, which is surrounded by a relatively large volume of baseline solution. Thus, and as is also noted in Sibbald, the outflow of baseline solution must be much greater than that of the warm analyte (a 3 to 1 ratio is disclosed) to effectuate adequate heat exchange efficiency. The need for this type of arrangement not only generates severe restrictions on the design of the system, but also the utility and effectiveness of the system. It is also recognized in Sibbald that it is preferable to analyze the blood at body temperature, which, in accordance with the Sibbald system, is difficult. Additionally, Sibbald adds that monitoring more than four ionic species simultaneously creates considerable engineering difficulties. It is to these problems that the present invention is directed.
None of the prior art devices effectuates the objective of the present invention, i.e., utilization of less then 8 microliters of blood in the analyte chamber, with an overall total volume of analyte in transit of less then 20 microliters; an analysis cycle of less than one minute; a low cost, disposable sensor capable of analyzing efficiently numerous blood component concentrations; a piston actuator valve system devoid of electrically operated mechanisms; low cost, disposable tubing for the analyte; and, most importantly, a truly continuous on-line monitoring system whereby the patient's exsanguination is less then 20 cc/24 hours. Thus, the present invention allows for the precise measurement of the analyte ionic concentration over a continuous period of time, such that a proper analysis of discrete and drastic fluctuations can be made. In this way, critical data is continually provided to those responsible for the care of the patient.